title: Attenuation of plasma low density lipoprotein cholesterol by select 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in mice devoid of low density lipoprotein receptors.
abstract: Low density lipoprotein (LDL) reduction independent of LDL receptor regulation was investigated using HMG-CoA reductase inhibitors in LDL receptor-deficient mice. In males, LDL cholesterol dose-dependently decreased with atorvastatin treatment after 1 week. As untreated mice grew older, their LDL cholesterol progressively rose above basal levels, but was quelled with atorvastatin treatment. In females, atorvastatin treatment time-dependently decreased LDL cholesterol levels and induced hepatic HMG-CoA reductase activity. Unlike males, cholesterol-lowering effects of the drug were sustained in females. Lovastatin, simvastatin, and pravastatin also reduced total and LDL cholesterol; however, additional studies in females demonstrated that atorvastatin caused the greatest dose-dependent and sustained effect after 2 weeks. In females, hepatic HMG-CoA reductase mRNA inversely correlated with LDL cholesterol lowering, with atorvastatin showing the greatest increase in mRNA levels (17.2-fold), followed by lovastatin (10.7-fold), simvastatin (4.1-fold), and pravastatin (2.5-fold). Atorvastatin effects on lipoprotein production were determined after acute (1 day) or chronic (2 week) treatment prior to intraperitoneal injection of Triton WR1339. Acute treatment reduced cholesterol (-29%) and apoB (-16%) secretion, with no change in triglyceride secretion. In contrast, chronic treatment elevated cholesterol (+20%), apoB (+31%), and triglyceride (+57%) secretion. Despite increased cholesterol and apoB secretion, plasma levels were reduced by 51% and 46%, respectively. Overall, under acute or chronic conditions, apoB paralleled cholesterol secretion rates, and triglyceride to cholesterol secretion ratios were elevated by 38% and 32%, respectively. We propose that atorvastatin limits cholesterol for lipoprotein assembly, which is compensated for by triglyceride enrichment. In addition, with either acute or chronic atorvastatin treatment, apoB-100 secretion was blocked, and compensated for by an increased secretion of apoB-48. The apoB-48 particles produced are cleared by LDL receptor-independent mechanisms, with an overall effect of reducing LDL production in these mice. These studies support the idea that HMG-CoA reductase inhibitors modulate lipoprotein levels independent of LDL receptors, and suggest they may have utility in hyperlipidemias caused by LDLreceptor disorders.
authors.affiliation: Department of Vascular and Cardiac Diseases, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Bisgaier
authors.forename: A D
authors.initials: AD
authors.lastname: Essenburg
authors.forename: B J
authors.initials: BJ
authors.lastname: Auerbach
authors.forename: M E
authors.initials: ME
authors.lastname: Pape
authors.forename: C S
authors.initials: CS
authors.lastname: Sekerke
authors.forename: A
authors.initials: A
authors.lastname: Gee
authors.forename: S
authors.initials: S
authors.lastname: Wölle
authors.forename: R S
authors.initials: RS
authors.lastname: Newton
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001055:Apolipoproteins B / Q000097:blood; D002784:Cholesterol / Q000378:metabolism; D008078:Cholesterol, LDL / Q000378:metabolism*; D005260:Female; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D015151:Immunoblotting; D008074:Lipoproteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011092:Polyethylene Glycols / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency*; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism
chemical_list: D000924:Anticholesteremic Agents; D001055:Apolipoproteins B; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008074:Lipoproteins; D012333:RNA, Messenger; D011973:Receptors, LDL; D014280:Triglycerides; D011092:Polyethylene Glycols; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; C016811:tyloxapol